β-agonists are a class of sympathomimetic agents which act upon the β adrenoceptors that relax muscles of the airways and results in easier breathing.
Clenbuterol (CL) is an extremely potent β-agonist with preferential affinity for β2-adrenoceptor of the bronchial and uterine smooth muscle. Clinical trials have however revealed that the selectivity of CL for bronchodilation is not absolute and even at “therapeutic doses” this β-agonist can activate β1-adrenoceptors in the myocardium (causing palpitation) as well as β2-adrenoceptors in the central nervous system (causing tremors and headaches). (Can Vet J Volume 35, August 1994, 474, http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1686713/pdf/canvetj00357-0012.pdf). The drug is used in the form of oral tablets, granules and dry syrup for the treatment of bronchial asthma in humans in many countries. CL HCl preparations are being used in children as well as adults. Majorly, the drug is being used for veterinary asthma.
U.S. Pat. No. 3,536,712 describes the synthesis of Clenbuterol HCl from 1-(4′amino-phenyl)-2-(t-butyl-amino)-ethanol, hydrogen chloride and chlorine. Other methods use nitro acetophenone or tertiary butyl phenyl ethanol as starting material. In the first method, reduction of nitro group to amino group and chlorination at 3 and 5 positions on the phenyl ring is needed. Also, for addition of the tertiary butylamino group, a bromination step is needed earlier. In the second method, amino group cannot be added directly onto the phenyl ring, nitro group needs to be added, which is then reduced to amino group. Moreover, the process uses phosgene, which is a poisonous gas.
Therefore, there is a need for a process that avoids the use of poisonous materials in the synthesis steps of β-agonists.